HIV-infected macrophages and microglia secrete neurotoxins that induce dementia in virus-infected patients during advanced immunosuppression. The mechanism(s) for how HIV gains entry into the brain, nevertheless, remain poorly understood. Productive viral replication in brain endothelium and/or upregulation of adhesion molecules on brain microvascular endothelial cells (BMVEC) could permit viral entry. In order to investigate the relative contribution of both mechanisms for HIV entry into brain we inoculated primary human BMVEC with HIV-1 or cocultured the cells with virus-infected monocytes. In both instances BMVEC failed to demonstrate sustained productive viral replication. However, E-selectin was readily expressed in brain endothelium following its interactions with HIV-infected monocytes. BMVEC cocultured with activated HIV-infected monocytes expressed even higher levels of E-selectin and vascular cell adhesion molecule-1 (VCAM-1). To verify the in vivo relevance of these findings, levels of adhesion molecules were compared with cytokines and HIV-1 gene products in brain tissue of AIDS patients without encephalitis. HIV-seronegative brain tissue served as controls. E-selectin and to a lesser degree VCAM-1 closely paralleled the levels of HIV-1 gene products and cytokines in brain tissue of subjects with HIV encephalitis. These data, taken together, strongly suggest that HIV entry into brain is a consequence